The prevalence of obesity in North America and in most European countries has more than doubled in the last 20 years and over half of the adult population are now either overweight or obese. Obesity is now recognized as a chronic disease and a critical global health issue (Fiegal et al, 1998, Int. J. Obesity 22:39-47, Mokdad et al, 1999, JAMA 282:1519-1522; Halford, 2006, Appetite, 46, 6-10). The “identifiable signs and symptoms” of obesity include an excess accumulation of fat or adipose tissue, an increase in the size or number of fat cells (adipocyte differentiation), insulin resistance, increased glucose levels (hyperglycemia), increased blood pressure, elevated cholesterol and triglyceride levels and decreased levels of high-density lipoprotein. Obesity is associated with a significantly elevated risk for type 2 diabetes, coronary heart disease, stroke, hypertension, various types of cancer and numerous other major illnesses, and overall mortality from all causes (Must et al,1999, JAMA 282:1523-1529, Calle et al, 1999, N. Engl. J. Med. 341:1097-1105). A cluster of metabolic risk factors for cardiovascular disease and type 2 diabetes is often referred to as metabolic syndrome, syndrome X or insulin resistance syndrome. The major components of metabolic syndrome X include excess abdominal fat (also known as visceral, male-pattern or apple-shaped adiposity), atherogenic dyslipidemia (decreased high-density lipoprotein cholesterol (HDL-C)), elevated triglycerides), hypertension, hyperglycaemia (diabetes mellitus type 2 or impaired fasting glucose, impaired glucose tolerance, or insulin resistance), a proinflammatory state and a prothrombotic state.(cf. AHA/NHLBI/ADA Conference Proceedings, Circulation 2004; 109:551-556). Other abnormalities often associated with the metabolic syndrome include increased apolipoprotein B concentrations, low adiponectin plasma levels, small dense low-density lipoprotein (LDL) particles, hyperuricaemia, non-alcoholic fatty liver disease/hepatic steatosis, elevated liver transaminases, gamma-glutamyl-transferase and microalbuminuria.
Like obesity, the prevalence of obesity-related diseases such as diabetes also continues to rise. Weight reduction is critical for the obese patient as it can improve cardiovascular and metabolic values to reduce obesity-related morbidity and mortality (Blackburn, 1999, Am. J. Clin. Nujtr. 69:347-349, Galuska et al, 1999, JAMA 282:1576). It has been shown that 5-10% loss of body weight can substantially improve metabolic parameters such as levels of fasting and post-prandial blood glucose, HbA1c (glycosylated haemoglobin), insulin, total plasma cholesterol, low density lipoproteins (LDL), triglyceride, uric acid and blood pressure and reduce the risk for development of diabetes, cancer and cardiovascular diseases (Goldstein, 1992, J. Obesity, 6, 397-415).
Thus, a primary aim of treatment for obesity, and obesity-related disorders, is weight loss. Initially, treatments are based on diet and lifestyle changes augmented by therapy with pharmacological therapies. However, while physical exercise and reductions in dietary intake of calories can improve the obese condition, compliance with this treatment is very poor because of sedentary lifestyles and excess food consumption, especially high fat containing food. Additionally, treatment with the available pharmacological therapies to facilitate weight loss fail to provide adequate benefit to many obese patients because of experienced side effects, contraindications, or lack of positive response. Hence, there is impetus for developing new and alternative treatments for management of obesity.
Several potential anti-obesity agents are currently investigated (for a review, see Bays, 2004, ObesityResearch, 12, 1197-1211)such as                i) central nervous system agents that affect neurotransmitters or neural ion channels (e.g. antidepressants (bupropion), noradrenaline reuptake inhibitors (GW320659), selective 5HT 2c receptor agonists, antiseizure agents (topiramate, zonisamide), some dopamine antagonists, cannabinoid CB-1 receptor antagonists (rimonabant);        ii) leptin/insulin/central nervous system pathway agents (e.g. leptin analogues, leptin transport and/or receptor promoters, CNTF (Axokine), NPY antagonists, AgRP antagonists, POMC promoters, CART promoters, MSH analogues, MC4 receptor agonists, agents that affect insulin metabolism/activity [PTP-1B inhibitors, PPAR receptor antagonists, short-acting D2 agonist (ergoset), somatostatin agonists (octreotide), and adiponectin/Acrp30 (Famoxin or Fatty Acid Metabolic OXidation INducer)]);        iii) gastrointestinal-neural pathway agents (e.g. agents that increase CCK and PYY activity, agents that increase GLP-1 activity (extendin 4, liraglutide, dipeptidyl peptidase IV inhibitor), agents that decrease ghrelin activity, amylin (pramlinitide), neuropeptide Y agonists);        iv) agents that may increase resting metabolic rate (beta-3 agonists, UCP homologues, thyroid receptor agonists); and        v) other more diverse agents, such as for example including (MCH) melanin concentrating hormone antagonists, phytostanol analogues, functional oils, P57, amylase inhibitors, growth hormone fragments, synthetic analogues of DHEAS (fluasterone), antagonists of adipocyte 11beta-hydroxysteroid dehydrogenase type 1 activity, CRH agonists, carboxypeptidase inhibitors, inhibitors of fatty acid synthesis (cerulenin and C75), indanones/indanols, aminosterols (trodusquemine), and other gastrointestinal lipase inhibitors (ATL962).        
Drugs effective in obesity treatment may act by various mechanisms such as by: a reduction of food intake (e.g. by inducing satiety or satiety signals), altering metabolism (e.g. by modifying the absorption of nutrients e.g. by inhibition of fat absorption), increasing energy expenditure (e.g. increase thermogenesis), inhibition of lipogenesis or stimulation of adipocyte apoptosis. However, only few drugs are available for obesity treatment (for reviews, see Gadde and Allison, 2006, Circulation, 114, 974-984; Weigle, 2003, J Clin Endocrinol Metab., 88, 2462-2469; Schiöth, 2006, CNS Neurol. Disorders Drug Targets, 5, 241-249). Sibutramine is a centrally acting mixed inhibitor of serotonin and norepinephrine presynaptic re-uptake. Orlistat is an inhibitor of gastrointestinal lipases which reduces fat absorption in the gut. Rimonabant (SR141716, Acomplia®) is a centrally and peripherally acting cannabinoid CB1 modulator (antagonist and inverse agonist) that recently has been approved for treatment of obesity (for a review see Pagotto et al, 2006, Endocrine Reviews, 27, 73-100; for reports on phase III clinical trials see Despres et al, 2005, N. Engl. J. Med. 353, 212; van Gaal et al, 2005, Lancet, 16, 1389; Pi-Sunyer et al, 2006, JAMA, 295, 761).
Presently, two cannabinoid receptors have been characterized: CB1, a receptor found in the mammalian brain and in a number of other sites in peripheral tissues; and CB2, a peripheral receptor found principally in cells related to the immune system. For reviews on cannabinoid CB1 and CB2 receptor modulators, see Pertwee, 2000, Exp. Opin. Invest. Drugs, 9, 1553-1571 and Muccioli, 2005, Cur. Med. Chem., 12, 1361-1394. A substantial body of evidence indicates that CB1 antagonists (e.g. rimonabant) are able to modulate energy homeostasis and that CB1 antagonists are able to modulate food intake as well as peripherally block lipogenic processes (Pagotto et al, 2006, Endocrine Reviews, 27, 73-100; Tucci et al, 2006, Curr. Med. Chem. 13, 2669-2680; Lange and Kruse, 2004, Current Opinion in Drug Discovery & Dev., 7, 498-506). The peripheral effects of CB1 antagonists can be mediated by several target organs and mechanisms, e.g. i) liver: block of de novo lipogenesis, ii) muscles: increase in glucose uptake, iii) adipose tissue: stimulation of expression and/or secretion of adiponectin, inhibition of lipogenic enzymes, stimulation of GLUT4, generation of futile cycles, iv) pancreas: insulin regulation and v) gastrointestinal tract: stimulation of satiety signals.
Rimonabant (Acomplia®) is approved as an adjunct to diet and exercise for treatment of obesity. While the effects on body weight and metabolic parameters (plasma triglyceride levels, HDL cholesterol levels, plasma insulin levels, HbA1c [glycosylated haemoglobin] levels, insulin resistance, and adiponectin levels) are very encouraging, there are also undesirable side effects, possibly centrally mediated (psychiatric and nervous system disorders), such as anxiety, depressive disorders, sleep disorders, nausea, and vomiting (cf. http://emc.medicines.org.uk;
http://www.emea.europa.eu/humandocs/PDFs/EPAR/acomplia/AcompliaEparScientificD-en.pdf). Accordingly, there still exists a need for alternative CB1 receptor antagonists associated with differing pharmacokinetic, pharmacological, and side-effect profiles.
The CB1 receptor has been invoked in many disease states (cf. review by Pacher et al, 2006, Pharmacol. Rev, 58, 389-462). Modulators of CB1 receptor activity can be useful in the treatment of diseases and conditions associated with CB1 receptor regulation such as obesity and overweight, prevention of weight gain (e.g. induced by medications or smoking cessation), and in the treatment of diseases and conditions directly or indirectly associated with obesity (cf. Bray, 2004, J. Clin. Endocrinol. Metab. 89, 2583-9; Manson, et al, 1995, N. Engl. J. Med. 333, 677-85; Grundy, 2004,.J. Clin. Endocrinol. Metab. 89, 2595-600; Esposito et al, 2004, JAMA 291; 2978-84; Ejerblad et al, 2006; J. Am. Soc. Nephrol. 17, 695-702; Whitmer et al, 2005, BMJ 330 (7504),1360) such as                metabolic syndrome, also referred to as syndrome X or insulin resistance syndrome,        type 2 diabetes,        cardiovascular diseases (e.g. aneurysms, angina, arrhythmia, atherosclerosis, cardiomyopathy, cerebrovascular accident (stroke), cerebrovascular disease, congenital heart disease, congestive heart failure, myocarditis, valve disease, coronary artery disease, dilated cardiomyopathy, diastolic dysfunction, endocarditis, high blood pressure (hypertension), hypertrophic cardiomyopathy and its associated arrhythmias and dizziness, mitral valve prolapse, myocardial infarction (heart attack), venous thromboembolism, varicose veins and pulmonary embolism, proinflammatory state, increased tendency to thrombosis (prothrombotic state), and intracranial hypertension,        metabolic dysfunctions in obese, overweight or normoweight individuals (e.g. dyslipidemia, hyperlipidemia, low HDL and/or high LDL cholesterol levels, hypertriglycerideemia, low adiponectin levels, impaired glucose tolerance, insulin resistance, increase in HbA1c [glycosylated haemoglobin] levels, diabetes mellitus, type 2 diabetes, reduced metabolic activity),        metabolic diseases or disorders (conditions in which there is a deviation from or caused by an abnormal metabolic process; can be congenital due to inherited enzyme abnormality or acquired due to disease of an endocrine organ or failure of a metabolically important organ such as the liver.),        cancers (e.g. colorectal cancer, breast cancer, uterine cancer, colon cancer),        liver diseases (e.g. non-alcoholic fatty liver disease, steatohepatitis, steatosis, hepatic fibrosis, hepatic cirrhosis), and        other secondary diseases related to obesity and overweight, such as menstrual disorders, gastroesophageal reflux disease, cholelithiasis (gallstones), hernia, urinary incontinence, chronic renal failure, hypogonadism (male), stillbirth, stretch marks, acanthosis nigricans, lymphedema, cellulitis, carbuncles, intertrigo, hyperuricemia, immobility, osteoarthritis, low back pain, meralgia paresthetica, headache, carpal tunnel syndrome, dementia, idiopathic dyspnea, obstructive sleep apnea, hypoventilation syndrome, Pickwickian syndrome, asthma, depression, low self esteem, body dysmorphic disorder, social stigmatization.        
The CB1 receptor has been invoked in many disease states diseases not necessarily related to obesity and overweight such as                eating disorders,        addictive disorders (e.g. addiction to marijuana, psychostimulants, nicotine, alcohol, cocaine, and opiates),        mental disorders (e.g. schizophrenia, schizo-affective disorder, bipolar disorders, anxiety, panic disorder),        neurological disorders,        sexual dysfunctions (e.g. erectile dysfunction),        reproductive dysfunctions (e.g. polycystic ovarian syndrome, infertility),        liver diseases (e.g., viral hepatitis, liver dysfunction in other infectious diseases, inflammatory liver diseases (e.g. autoimmune hepatitis), alcoholic liver disease, toxic liver disease, liver tumors (such as liver cell carcinoma, hepatocellular carcinoma, hepatoma, cholangiocarcinoma, hepatoblastoma, angiosarcoma of liver, Kupffer cell sarcoma, other sarcomas of liver), steatohepatitis, non-alcoholic fatty liver disease hepatic fibrosis, hepatic cirrhosis, cirrhotic portal hypertension, metabolic liver diseases (such as haemochromatosis, Wilson's disease, Gilbert's syndrome, Crigler-Najjar syndrome, Dubin-Johnson syndrome, Rotor's syndrome)),        fibrosis-related diseases (such as cystic fibrosis of the pancreas and lungs, endomyocardial fibrosis, idiopathic myocardiopathy, idiopathic pulmonary fibrosis of the lung, diffuse parenchymal lung disease, mediastinal fibrosis, myleofibrosis, post-vasectomy pain syndrome, retroperitoneal fibrosis, progressive massive fibrosis, proliferative fibrosis, neoplastic fibrosis, sickle-cell anemia may cause enlargement and ultimately fibrosis of the spleen),        and other clinical indications such as epilepsy, osteoporosis, rheumatoid arthritis, inflammatory bowel disease (ulcerative colitis (UC) and Crohn disease (CD), congestive obstructive pulmonary disease (COPD), inflammation, inflammatory pain, atherosclerosis, diarrhoea, asthma, constipation, skin diseases, glaucoma and hairloss.        
Since obesity leads to, or significantly increases the risk of, co-morbidities involving various body systems (see Bays, 2004, Obesity Research, 12, 1197-1211) including:                i) cardiovascular (hypertension, congestive cardiomyopathy, varicosities, pulmonary embolism, coronary heart disease [CHD], neurological (stroke, idiopathic intracranial hypertension, meralgia parethetica),        ii) respiratory (dyspnea, obstructive sleep apnea, hypoventilation syndrome, Pickwickian syndrome, asthma),        iii) musculoskeletal (immobility, degenerative osteoarthritis, low back pain),        iv) skin (striae distensae or “stretch marks,” venous stasis of the lower extremities, lymphedema, cellulitis, intertrigo, carbuncles, acanthosis nigricans, skin tags),        v) gastrointestinal (gastro-esophageal reflux disorder, non-alcoholic fatty liver/steatohepatitis, cholelithiasis, hernias, colon cancer),        vi) genitourinary (stress incontinence, obesity-related glomerulopathy, breast and uterine cancer),        vii) psychological (depression and low self-esteem, impaired quality of life), and        viii) endocrine (metabolic syndrome, type 2 diabetes, dyslipidemia, hyperandrogenemia in women, polycystic ovarian syndrome, dysmenorrhea, infertility, pregnancy complications, male hypogonadism)it is also useful to combine a CB1 modulator with medications used for treatment of such diseases. It is also useful to combine a CB1 modulator with medications used for treatment of diseases which may be unrelated to obesity such as eating disorders, addictive disorders, mental disorders, neurological disorders, sexual dysfunctions, reproductive dysfunctions, liver diseases, fibrosis-related diseases, and other clinical indications which may be unrelated to obesity.        